IL-17 produced by neutrophils regulates IFN-γ-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury
IL-17 produced by neutrophils regulates IFN-γ-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury
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DOI：
10.1172/jci38702
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发表时间：
2010-01-01
影响因子：
15.9
通讯作者：
Okusa, Mark D.
中科院分区：
文献类型：
--
作者：
Li, Li;Huang, Liping;Okusa, Mark D.
IL-23/IL-17和IL-12/IFN-γ细胞因子途径在慢性自身免疫中发挥作用，这主要被认为是适应性免疫功能障碍。然而，它们对先天免疫的贡献程度尚不清楚。我们使用急性肾缺血再灌注损伤 (IRI) 小鼠模型来检验以下假设：1111 之后早期产生 IL-23 和 IL-12 会激活下游 IL-17 和 IFN-gamma 信号通路并促进肾脏炎症。 IL-23、IL-17A 或 IL-17 受体 (IL-17R) 缺乏以及 CXCR2（IL-23 的 p19 亚基）或 IL-17A 的 mAb 中和可减弱小鼠急性肾 IRI 中的中性粒细胞浸润。我们进一步证明 GR-1(+) 中性粒细胞产生的 IL-17A 对于小鼠肾脏 IRI 至关重要。通过施用α-半乳糖苷神经酰胺引发的骨髓来源的DC来激活IL-12/IFN-γ途径和NKT细胞，增加了WT小鼠中度IRI后IFN-γ的产生，但没有加剧Il17a(-/-)或Il17r(-/-)小鼠的损伤或增强IFN-γ的产生，这表明IL-17 信号传导最接近 IFN-γ 信号传导。 IFN-gamma 给药逆转了受到 IRI 的 Il17a(-/-) 小鼠中观察到的保护作用，而 IL-17A 未能逆转 Ifng(-/-) 小鼠中的保护作用，这一发现证实了这一点。这些结果表明，肾脏IRI的先天免疫成分需要IL-12/IFN-γ和IL-23/IL-17信号通路的双重激活，并且IL-17A的中性粒细胞产生是IL-12/IFN-γ的上游。这些机制可能导致其他器官的再灌注损伤。
The IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways have a role in chronic autoimmunity, which is considered mainly a dysfunction of adaptive immunity. The extent to which they contribute to innate immunity is, however, unknown. We used a mouse model of acute kidney ischemia-reperfusion injury (IRI) to test the hypothesis that early production of IL-23 and IL-12 following 1111 activates downstream IL-17 and IFN-gamma signaling pathways and promotes kidney inflammation. Deficiency in IL-23, IL-17A, or IL-17 receptor (IL-17R) and mAb neutralization of CXCR2, the p19 subunit of IL-23, or IL-17A attenuated neutrophil infiltration in acute kidney IRI in mice. We further demonstrate that IL-17A produced by GR-1(+) neutrophils was critical for kidney IRI in mice. Activation of the IL-12/IFN-gamma pathway and NKT cells by administering alpha-galactosylceramide-primed bone marrow-derived DCs increased IFN-gamma production following moderate IRI in WT mice but did not exacerbate injury or enhance IFN-gamma production in either Il17a(-/-) or Il17r(-/-) mice, which suggested that IL-17 signaling was proximal to IFN-gamma signaling. This was confirmed by the finding that IFN-gamma administration reversed the protection seen in Il17a(-/-) mice subjected to IRI, whereas IL-17A failed to reverse protection in Ifng(-/-) mice. These results demonstrate that the innate immune component of kidney IRI requires dual activation of the IL-12/IFN-gamma and IL-23/IL-17 signaling pathways and that neutrophil production of IL-17A is upstream of IL-12/IFN-gamma. These mechanisms might contribute to reperfusion injury in other organs.